We propose a Phase I/II clinical trial to assess the safety and efficacy of transplanting autologous bone marrow CD34+ cells transduced with the EFS-ADA lentiviral vector (LV) following non-myeloablative conditioning with busulfan chemotherapy. Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID) has been treated using ?-retroviral (?-RV)-mediated gene transfer to bone marrow CD34+ hematopioetic stem cells (HSC) in recent clinical trials. Stable engraftment of gene-corrected HSC has been achieved with in vivo expression of ADA enzyme activity in blood cells and substantial immune reconstitution in the majority of subjects. However, the pace of lymphocyte recovery is relatively slow and the absolute levels of lymphocytes reached are often sub-normal, and the majority of subjects do not have effective B cell reconstitution and immunoglobulin production. The efficiency of gene transfer to human HSC using ?-RV is moderate, limited in part by the relatively low titers of these vectors when made at clinical scale. Additionally, ?-RVs have the potential for causing insertional oncogenesis by insertion of their strong enhancer elements adjacent to cellular proto-oncogenes. Lentiviral vectors (LV) can be configured to have minimal enhancer activity in the transcriptional units and may be safer than ?-RV. Also, LV may transfer genes more efficiently to human HSC in a shorter time of culture preserving stem cell engraftment capacity. This trial will test the hypothesis that: the EFS-ADA lentiviral vector will safely lead to more engrafted, transduced HSC with better immune reconstitution compared to a historical control group in prior trials using ?-retroviral vectors (?-RV). This 5-year study will enroll 10 ADA-deficient SCID patients through two sites (UCLA and NIH). Three to four patients will be enrolled annually during a 3-year accrual period and each patient will be followed for two years. There will be a separate study for long-term follow-up for these patients for years 3-15. If successful, this approach may lead to an alternative therapeutic approach to patients with ADA-deficient SCID, and other primary immune deficiencies and blood cell diseases.